Processes for preparing darifenacin hydrobromide

ABSTRACT

The invention encompasses processes for the preparation of darifenacin hydrobromide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/647,109,filed Dec. 27, 2006, which claims the benefit of priority to U.S.Provisional Application Ser. Nos. 60/754,395, filed Dec. 27, 2005;60/772,250, filed Feb. 9, 2006; 60/776,311, filed Feb. 23, 2006;60/809,147, filed May 25, 2006; 60/813,579, filed Jun. 8, 2006;60/836,557, filed Aug. 8, 2006; 60/837,407, filed Aug. 10, 2006;60/850,184, filed Oct. 5, 2006; 60/859,332, filed Nov. 15, 2006; and60/873,680, filed Dec. 7, 2006, hereby incorporated by reference. Thisapplication is also related to U.S. application Ser. Nos. 11/646,919,filed Dec. 27, 2006 and entitled “Processes for Preparing DarifenacinHydrobromide;” and 11/646,915, filed Dec. 27, 2006 and entitled “PureDarifenacin Hydrobromide Substantially Free of Oxidized Darifenacin andSalts Thereof and Process for the Preparation Thereof,” herebyincorporated by reference.

FIELD OF THE INVENTION

The invention encompasses processes for the preparation of darifenacinhydrobromide.

BACKGROUND OF THE INVENTION

Darifenacin,(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide,a compound having the chemical structure,

is a selective M3 receptor antagonist. Blockade of destructor muscleactivity manifests in an increase in urine volume that the bladder canretain, reduction of urination frequency, and decrease in pressure andurgency associated with the urge to urinate, and thereby episodes ofincontinence are reduced.

Darifenacin is administered as the hydrobromide salt,(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamidehydrobromide, of the structure

and is marketed under the trade name ENABLEX® by Novartis.

U.S. Pat. No. 5,096,890, hereby incorporated by reference, disclosesthree routes for the synthesis of darifenacin hydrobromide; all of whichcomprise the cumbersome and hazardous Mitsunobu reaction, described inthe following Scheme.

Accordingly, 1-tosyl-3-(R)-pyrrolidinol is reacted with methyl tosylate,and with diethylazodicarboxylate (DEAD), a very dangerous reagent.Typically, the product is contaminated with triphenylphosphine oxide,which is very difficult to separate from the desired product. Moreover,other toxic and hazardous reagents, such as pyridine and NaH, are usedin other steps of the synthesis.

The process disclosed in U.S. publication No. 20003/0191176 for thepreparation of darifenacin hydrobromide requires the use of BF₃, whichis a toxic reagent.

Therefore, there is a need in the art for a process for the preparationof darifenacin hydrobromide that does not use toxic and dangerousreagents and that can be performed on an industrial scale. The presentinvention provides such processes.

SUMMARY OF THE INVENTION

The invention encompasses a process for preparing darifenacinhydrobromide. The process comprises: a) combining3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the groupconsisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof, a sulfonyl halide, and a base to obtain1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I, diphenylacetonitrile, and an inorganic base, in an organicsolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, toobtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II;

c) reacting the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrileintermediate of formula II, a bromine acceptor selected from the groupconsisting of phenol and naphthol, and an acid to obtain(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBr;d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt offormula III, a compound of the formula V,

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar organic solvent, water, and mixtures thereof, and abase to obtain a mixture;e) heating the mixture of step d;f) admixing the mixture of step d with an acid to obtain a(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV; and

g) admixing the(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV, an inorganic base and a protic solvent; andh) reacting with hydrobromic acid to obtain darifenacin hydrobromide,wherein X is either C₁₋₁₀alkyl or C₆₋₉ aryl, wherein Y is a leavinggroup selected from the group consisting of I, Cl, Br, mesyl, tosyl,brosyl, trifluoroacetyl, and trifluoromethansulfonyl, wherein Z₁ and Z₂are independently an acid.

The invention also encompasses a process for preparing a(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV,

comprising: a) combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrilesalt of formula III,

a compound of the formula V,

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar organic solvent, water, and mixtures thereof, and abase to form a mixture; b) heating the mixture of step b, and c)reacting the mixture of step b with an acid to obtain to obtain a(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV; wherein Z₁ and Z₂ are independently an acid; whereinY is a leaving group selected from the group consisting of I, Cl, Br,brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl.

The invention encompasses a process for preparing Darifenacinhydrobromide of the following formula

by a process comprising preparing a(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV by the process of the present invention, andconverting it to Darifenacin hydrobromide.

The invention also encompasses another process for preparing darifenacinhydrobromide.

The process comprises: a) combining 3-(S)-(+)-hydroxypyrrolidine, asolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, asulfonyl halide, and a base to obtain1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I, diphenylacetonitrile, and an inorganic base, in an organicsolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, toobtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II;

c) reacting the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrileintermediate of formula II, a bromine acceptor selected from the groupconsisting of phenol and naphthol, and an acid to obtain(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBr;

-   -   d) reacting the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile        salt of formula III with an inorganic base in a solvent selected        from the group consisting of a water immiscible organic solvent,        a polar aprotic organic solvent, water and mixtures thereof to        obtain a mixture;    -   e) acidifying the mixture of step d;    -   f) heating the mixture of step e;    -   g) basifying the mixture of step f to obtain        -   3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of formula            XI;

-   -   h) combining the        3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of formula XI,        2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII,

and a C₆₋₉ aromatic hydrocarbon to obtain a (S)-darifenamine of formulaVII;

-   -   i) admixing the (S)-darifenamine of formula VII with a C₁₋₈        alcohol and a reducing agent to obtain the (S)-darifenacin of        formula VIII; and

-   -   j) admixing the (S)-darifenacin of formula VIII with HBr to        obtain darifenacin hydrobromide, wherein X is either C₁₋₁₀alkyl        or C₆₋₉ aryl, preferably, C₆₋₉ aryl, more preferably, tolyl, and        Z₁ is an acid, preferably, either HBr or HCl.

The present further provides a process for the preparation of2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII

comprising: a) combining 2,3-dihydrobenzofura-5-yl-carboxyaldehyde offormula IX,

a C₂₋₄ alkylhaloacetate, an alkoxide, and an alkaline hydroxide toobtain the epoxide of the following formula;

b) admixing the epoxide with a solvent selected from a group consistingof C₆₋₉ aromatic hydrocarbons, C₁₋₂ halogenated hydrocarbons, water, andmixtures thereof, and an acid selected from a group consisting of H₃PO₄,acetic acid, HCl sulfonic acid, and HBr to obtain2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII.

The invention also encompasses2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde-bisulfite complex of formulaX.

The invention also encompasses a process for purifying2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII comprising: a)combining 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde, a water immisciblehydrocarbon, and Na₂S₂O₅ to form a mixture; and b) admixing with a baseto the mixture to obtain purified2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII.

The invention also encompasses (S)-darifenamine of formula VII

The invention also encompasses a process for preparing (S)-darifenamineof formula VII

comprising: combining 3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidineof formula XI,

2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII, and a C₆₋₉aromatic hydrocarbon to form obtain (S)-darifenamine of formula VII.

The present invention further provides the use of the new compound,(S)-Darifenamine of formula VII for the preparation of (S)-Darifenacinhydrobromide.

The present invention also provides a process for the preparation of(S)-Darifenacin hydrobromide comprising preparing (S)-Darifenamine offormula VII by the process of the present invention, and converting itto (S)-Darifenacin hydrobromide.

The invention also encompasses a process for preparing the(S)-darifenacin of formula VIII

comprising: combining (S)-darifenamine of formula VII,

a C₁₋₈ alcohol, and a reducing agent to obtain to obtain(S)-darifenamine of formula VII.

The present invention provides a process for the preparation of(S)-Darifenacin hydrobromide comprising preparing (S)-Darifenacin by theprocess of the present invention, and converting it to (S)-Darifenacinhydrobromide.

The invention also encompasses a process for preparing oxidizeddarifenacin hydrobromide comprising combining an oxidized derivative ofethyl-dihydrobenzofuran of the following formula

3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of the formula IX

an inorganic base and water; admixing with HBr to obtain oxidizeddarifenacin hydrobromide; wherein Y is a leaving group selected from thegroup consisting of I, Cl, brosyl, mesyl, tosyl, trifluoroacetyl, andtrifluoromethansulfonyl. Preferably, Y is Cl.

The invention also encompasses another process for the preparation ofdarifenacin hydrobromide comprising: a) combining an oxidized derivativeof ethyl-dihydrobenzofuran of the following formula

3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of the formula IX

an inorganic base and water; b) admixing with HBr to obtain oxidizeddarifenacin hydrobromide, and c) admixing with a reducing agent toobtain darifenacin hydrobromide; wherein Y is a leaving group selectedfrom the group consisting of I, Cl, brosyl, mesyl, tosyl,trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is Cl.

The present invention encompasses a process for preparing Darifenacinhydrobromide by a process comprising preparing oxidized Darifenacinhydrobromide by the process of the present invention, and converting itto Darifenacin hydrobromide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for preparingDarifenacin hydrobromide; wherein the cumbersome Mitsunobu reaction isavoided. Also, the synthesis can be scaled up, minimizing productionhazards.

The invention encompasses a process for the preparation of darifenacinhydrobromide, comprising: a) combining 3-(S)-(+)-hydroxypyrrolidine, asolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, asulfonyl halide, and a base to obtain1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I, diphenylacetonitrile, and an inorganic base, in an organicsolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, toobtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II;

c) reacting the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrileintermediate of formula II, a bromine acceptor selected from the groupconsisting of phenol and naphthol, and an acid to obtain(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBr;d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt offormula III, a compound of the formula V,

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar organic solvent, water, and mixtures thereof, and abase to obtain a mixture;e) heating the mixture of step d;f) admixing the mixture of step d with an acid to obtain a(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV; and

g) admixing the(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV, an inorganic base and a protic solvent; andh) reacting with hydrobromic acid to obtain darifenacin hydrobromide,wherein X is either C₁₋₁₀alkyl or C₆₋₉ aryl, wherein Y is a leavinggroup selected from the group consisting of I, Cl, Br, mesyl, tosyl,brosyl, trifluoroacetyl, and trifluoromethansulfonyl, wherein Z₁ and Z₂are independently an acid.

The process can be described by the following scheme:

wherein X, Y, Z₁ and Z₂ are described before.

Preferably, X is C₆₋₉ aryl, more preferably, tolyl. Preferably, Y is Cl.Preferably, the acid, is either HBr or HCl.

The N—O-sulfonation reaction of the present invention is performed usingsolvents, which are not hazardous and toxic, as compared to pyridinethat is used in U.S. Pat. No. 5,096,890. Also, the reaction is muchshorter, and leads to a much higher yield, 96% vs. 75%. Moreover, theproduct is isolated very easily from a mixture of toluene and water, ascompared to the difficult isolation performed in U.S. Pat. No.5,096,890, which includes recovering the product by time consumingsteps, such as distillation of pyridine, extractions withdichloromethane, and crystallization from n-propanol. Hence, thesulfonation reaction limits the process from being scaled up.

The intermediate of formula I,1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine

is prepared by a process comprising combining3-(S)-(+)-hydroxypyrrolidine of the following formula,

3-(S)-(+)-hydroxypyrrolidine

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, asulfonyl halide, and a base; wherein X is either C₁₋₁₀ alkyl or C₆₋₉aryl. Preferably, X is C₆₋₉ aryl, and more preferably tolyl.

Typically, the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I is obtained by the above process in a purity of about 95% toabout 99% area by HPLC.

The starting material, 3-(S)-(+)-hydroxypyrrolidine is commerciallyavailable.

Typically, combining the 3-(S)-(+)-hydroxypyrrolidine and the solventprovides a solution. The sulfonyl halide is then added to the solutionto form a mixture. The addition of the sulfonyl halide to the solutionleads to a rise in the temperature of the solution, typically to about35° C. to about 40° C. Preferably, the base is then added to the mixtureto form a reaction mixture, which leads to a second rise in temperature,typically to about 50° C. to about 60° C. Preferably, after the base isadded, the reaction mixture is maintained at a temperature of about 25°C. to about reflux, more preferably, at about 50° C. to about 55° C.After the addition of the base, the reaction mixture is maintained forabout 2 to about 10 hours, more preferably, for about 4 to about 6hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene or o-, m-, orp-xylene. Preferably, the polar aprotic organic solvent is a C₁₋₁₀halogenated aliphatic hydrocarbon, amide, or sulfoxide. A preferredC₁₋₁₀halogenated aliphatic hydrocarbon is a C₁₋₅ halogenatedhydrocarbon, and more preferably dichloromethane (referred to as DCM),1,2,dichloroethane or dichloropentane. Preferably, the amide is eitherdimethylformamide (referred to as DMF) or dimethylacetamide (referred toas DMA). Preferably, the sulfoxide is a C₁₋₄ sulfoxide, and morepreferably dimethylsulfoxide (referred to as DMSO). The more preferredsolvent is toluene.

Optionally, a phase transfer catalyst (referred to as PTC) may be usedto increase the reaction rate. When the solvent is a C₆₋₉ aromatichydrocarbon, preferably, a phase transfer catalyst is used. Preferably,the PTC is added to the solution of 3-(S)-(+)-hydroxypyrrolidine priorto the addition of the sulfonyl halide. Preferably, the PTC is selectedfrom the group consisting of tetrabutylammonium bromide, ALIQUAT®tributylmethylammonium chloride, tetrabutylammonium sulfate, and DMSO,and more preferably tetrabutylammonium bromide.

Preferably, the halide moiety of the sulfonyl halide is selected fromchloride, bromide, and iodide, and more preferably chloride. Preferably,the sulfonyl halide is tosylchloride, mesylchloride, or brosylchloride,and more preferably tosylchloride. Preferably, the sulfonyl halide isadded portion-wise.

Preferably, the base is either an inorganic base or an organic base. Apreferred organic base is selected from the group consisting ofaliphatic and aromatic amines. Preferably, the aliphatic amine istriethylamine, methylmorpholine, or N,N-diisopropylethyl amine. Apreferred aromatic amine is pyridine. The inorganic base is added,preferably, in a form of an aqueous solution. The aqueous solutioncontains, preferably, an alkali base, and more preferably either sodiumhydroxide or potassium hydroxide. Preferably, the base is added slowly,more preferably over about a half an hour to about two hours, and evenmore preferably over about one hour.

The process for preparing1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I may furthercomprise a recovery step. The1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine may be recovered by anymethod known to one of ordinary skill in the art. Such methods include,but are not limited to, adding water to the reaction mixture; coolingthe reaction mixture to obtain a precipitate of the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine, and filtering theprecipitate from the reaction mixture.

Preferably, the addition of water provides a suspension. Preferably, thesuspension is cooled to a temperature of about 20° C. to about −5° C.,and more preferably to about 5° C. to about 0° C., to induceprecipitation of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine.Preferably, the cooled suspension is maintained for at least about onehour, preferably, for about 1 to about 2 hours, to give a precipitate of1-X-sulfonyl-3-(S)-(31)-X-sulfonyloxypyrrolidine. The precipitate isthen filtered and dried.

The 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I thusobtained may then be converted to(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile II.

The intermediate of formula II,(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile

is prepared by a process comprising combining1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,diphenylacetonitrile, an organic solvent selected from the groupconsisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof, and an inorganic base; wherein X iseither C₁₋₁₀ alkyl or C₆₋₉ aryl. Preferably, X is C₆₋₉ aryl, and morepreferably tolyl.

(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of theformula II is obtained by the above process in a purity of about 95% toabout 99% area by HPLC, and more preferably about 99% to about 100% areaby HPLC.

Typically, combining the diphenylacetonitrile and the organic solventprovides a first mixture. The addition of the inorganic base to thefirst mixture typically causes the temperature of the first mixture torise to about 20° C. to about 40° C., and preferably to about 25° C. toabout 35° C. Preferably, the first mixture is cooled to a temperature ofabout 30° C. to about 15° C., and more preferably to a temperature ofabout 25° C. to about 15° C., prior to the addition of the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I. Typically,the addition of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I provides a second mixture. Preferably, the second mixture isheated to a temperature of about 50° C. to about 100° C., and morepreferably to a temperature of about 70° C. to about 75° C. The heatedsecond mixture is maintained, preferably, for about 3 to about 6 hours,and more preferably, for about 4 to about 5 hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. Preferably, thepolar aprotic organic solvent is either an amide or a sulfoxide. Apreferred amide is a C₁₋₂ amide, and more preferably either DMF or DMA.A preferred sulfoxide is a C₁₋₄ sulfoxide, and more preferably DMSO. Themore preferred organic solvent is DMF.

Preferably, the inorganic base is either a metal alkoxide or an alkalihydroxide. A preferred metal alkoxide is either sodium tert-butoxide orsodium methoxide. A preferred alkali hydroxide is either sodium orpotassium hydroxide. The more preferred inorganic base is a metalalkoxide, most preferably either sodium or potassium tert-butoxide.

The process for preparing(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formulaII may further comprise a recovery step. The recovery may be may be doneby a process comprising adding to the second mixture to a mixture ofwater and a solvent selected from the group consisting of toluene, DCM,ethyl acetate (referred to as EtOAc), butyl acetate (referred to asBuOAc), and n-butanol to form a mixture having an aqueous and an organicphase; separating the aqueous and organic phases; washing the organicphase with water; and concentrating the organic phase under reducedpressure to obtain a concentrated residue. The residue is then cooled toa temperature of about 10° C. to about −10° C., and preferably to about3° C. to about −3° C., to give a precipitate of(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile.

The (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II thus obtained may then be converted to(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III.

The intermediate of formula III,(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt, is prepared by aprocess comprising heating a mixture comprising the compound of formulaII, a bromine acceptor selected from phenol and naphthol and an acid,wherein the bromine acceptor is phenol only when the acid is HBr.Preferably, the mixture is heated to a temperature of about 80° C. toabout 120° C., more preferably, to about 117° C. to about 120° C.Preferably, the heated mixture is maintained for about 1 hour to about 2hours, more preferably, for about 1 hour to about 1.5 hours. Preferably,the acid is HBr, H₂SO₄, H₃PO₄, HClO₄, or CF₃SO₃H, and more preferablyHBr. When using HBr as the acid, it is added in a form of an aqueoussolution, having a concentration of about 30% to about 60%, morepreferably, of about 48% to about 60%.

The (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula IIImay be recovered by a process comprising cooling the mixture to atemperature of about 30° C. to about 15° C., more preferably, to atemperature of about 30° C. to about 25° C., followed by extracting witha C₁₋₁₀ halogenated aliphatic hydrocarbon, and washing with brine. Theorganic phase is then concentrated under reduced pressure to give aresidue containing the compound of formula III and the solvent.Preferably, the C₁₋₁₀halogenated aliphatic hydrocarbon is a C₁₋₅halogenated hydrocarbon, more preferably, a C₁₋₃ halogenatedhydrocarbon. Most preferably, the C₁₋₃ halogenated hydrocarbon isselected from the group consisting of DCM, chloroform, dichloroethane,1,1-dichloroethane, and 1,5-dichloropentane. The residue is thencombined with a second solvent selected from the group consisting ofBuOAc, toluene, acetone, 2-butanone, and diisopropylether, followed by acomplete removal of the C₁₋₁₀ halogenated aliphatic hydrocarbon,preferably, by distillation, to give a second residue.

The second residue, containing the compound of formula III and a solventselected form the group consisting of BuOAc, toluene, acetone,2-butanone, and diisopropylether can be purified by a crystallizationprocess from a solvent selected from the group consisting of C₁₋₁₀ester,C₁₋₁₀ketone, C₁₋₁₀ether, C₁₋₁₀aliphatic hydrocarbon, C₆₋₉ aromatichydrocarbon, and mixtures thereof. Preferably, the C₁₋₁₀ ester isethylacetate, n-butylacetate, i-butylacetate, or n-propylacetate, morepreferably, ethylacetate. Preferably, the C₁₋₁₀ ketone is acetone,2-butanone, methyl-isobutylketone, or cyclohexanone. A preferredC₁₋₁₀ether is diethylether, diisopropylether, dibutylether, or methylisobutylether. Preferably, the C₁₋₁₀aliphatic hydrocarbon is pentane,hexanes, heptanes, or petroleum ether. Preferably, the C₆₋₉ aromatichydrocarbon is toluene or xylenes. Preferably, a mixture of EtOAc andhexane is used.

The compound of formula III thus obtained may then be converted to(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV.

The intermediate of formula IV,(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt,

is prepared by a process comprising: a) combining(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III,

a derivative of ethyl-dihydrobenzofuran of the formula V,

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar organic solvent, water, and mixtures thereof, and abase to obtain a mixture; b) heating the mixture of step b; and c)reacting the mixture of step c with an acid; wherein Z₁ and Z₂ areindependently an acid. Preferably, the acid is either HBr or HCl.

When Z₁ and Z₂ are HBr, the compound of formula III corresponds to(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile-hydrobromide of thefollowing formula,

and the compound of formula IV corresponds to(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile-hydrobromideof the following formula.

When Z₁ and Z₂ are HCl, the compound of formula III corresponds to(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile-hydrochloride of thefollowing formula,

and the compound of formula IV corresponds to(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-ppyrrolidinyl}-2,2-acetonitrile-hydrochlorideof the following formula.

Typically, the base and the solvent are combined, initially, to obtain afirst mixture. This mixture is then combined with(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III, andwith a derivative of ethyl-dihydrobenzofuran of the formula V, to obtaina second mixture, the mixture of step a. Preferably, the mixture of stepa is heated to a temperature of about 50° C. to about reflux, morepreferably, to a temperature of about 75° C. to about 80° C. Preferably,the heated mixture is maintained for about 3 hours to about 7 hours,where the following compound,

is expected to be formed. More preferably, the heated mixture ismaintained for about 4 hours to about 5 hours. The above compound may berecovered before the addition of the acid.

Preferably, the base is either an inorganic base or an organic base. Apreferred organic base is selected from the group consisting ofaliphatic and aromatic amines. Preferably, the aliphatic amine istriethylamine, tribytulamine, methylmorpholine, pyridine, orN,N-diisopropylethyl amine. When an inorganic base is used, it is in theform of an aqueous solution. A preferred inorganic base is an alkalihydroxide, alkali carbonate, alkali bicarbonate, or alkoxide. Apreferred alkali hydroxide is either sodium hydroxide or potassiumhydroxide. Preferably, an alkali carbonate is sodium carbonate orpotassium carbonate. Preferably, alkali bicarbonate is either sodiumbicarbonate or potassium bicarbonate. A preferred alkoxide is eithersodium methoxide or potassium methoxide. The more preferred base is analkali hydroxide, even more preferably, sodium hydroxide.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. A preferred polarorganic solvent is an amide, a sulfoxide, or a nitrile. Preferably, theamide is either DMF or DMA. Preferably, the sulfoxide is DMSO. Apreferred nitrile is acetonitrile (referred to as ACN). The morepreferred solvent is water.

The reaction may be monitored by HPLC.

The following compound

may be recovered by any method known to a skilled artisan. The recoverymay comprise cooling the mixture of step c; extracting the cooledmixture with a solvent selected from the group consisting of EtOAc,BuOAc, toluene, and n-butanol; washing the extract with water; andevaporating the solvent. Preferably, the mixture is cooled to atemperature of about 30° C. to about 15° C.

Preferably, the following compound

may be converted to the salt of formula IV directly, without isolation.When the conversion to the salt of formula IV is done directly, an acidis added to the organic phase, obtained by the above extractions,followed by cooling to a temperature of about 18° C. to about 15° C., toobtain a precipitate. The precipitate may be recovered by filtration,washing and drying.

The compound of formula V;

wherein Y is a leaving group selected from the group consisting of I,Cl, brosyl, Br, mesyl, tosyl, trifluoroacetyl, andtrifluoromethansulfonyl, preferably, Cl, used to prepare(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilesalt of formula IV, can be prepared according to a process comprising:a) combining 2(2,3-dihydrobenzofura-5-yl)-acetic acid of the followingformula:

a C₁₋₄ alcohol, and a catalyst to obtain2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester of the followingformula;

b) combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester areducing agent and a C₄₋₆ alcohol to obtain2(2,3-dihydrobenzofura-5-yl)-ethanol of the following formula;

c) combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol, a solventselected from the group consisting of a C₁₋₂ halogenated hydrocarbon,C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substance containing aleaving group selected from the group consisting of Cl, Br, mesyl,brosyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl to obtainthe compound of formula V; wherein Y is a leaving group selected fromthe group consisting of I, Cl, brosyl, Br, mesyl, tosyl,trifluoroacetyl, and trifluoromethansulfonyl.

The starting 2(2,3-dihydrobenzofura-5-yl)-acetic acid is commerciallyavailable.

Preferably, the C₁₋₄ alcohol, used in step a, is selected from the groupconsisting of methanol, ethanol, propanol, and butanol, and morepreferably methanol. Optionally, a mixture of solvents may be used instep a. Preferably, the mixture is that of C₁₋₄ alcohol and toluene, andmore preferably of methanol and toluene.

Preferably, the catalyst is an acid. Preferably, the acid is either anorganic or an inorganic acid selected from the group consisting ofsulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, HCl, HClO₄,and H₃PO₄. More preferably, the acid is an inorganic acid, and even morepreferably a mineral acid, and most preferably sulfuric acid.

The reaction between the 2(2,3-dihydrobenzofura-5-yl)-acetic acid, theC₁₋₄ alcohol and the catalyst may be performed with heating. Preferably,the heating is done to a temperature of about 60° C. to about 70° C.,and more preferably about 65° C. to about 70° C. Preferably, heating isdone for about 1 to about 5 hours, and more preferably for about 2 toabout 3 hours.

The reaction for preparing 2(2,3-dihydrobenzofura-5-yl)-acetic acidmethylester may further comprise a recovery step. The recovery may bedone by any method known to a skilled artisan. According to the processof the present invention, the recovery comprises adding a base to thereaction mixture comprising 2(2,3-dihydrobenzofura-5-yl)-acetic acidmethylester; removing the solvent; adding a C₆₋₉ aromatic hydrocarbon;washing with a basic solution; and removing the solvent. Preferably, thebase is sodium bicarbonate. Preferably, removing the solvent from thereaction mixture provides a residue. Preferably, the addition of a C₆₋₉aromatic hydrocarbon to the residue provides a solution. Preferably, theC₆₋₉ aromatic hydrocarbon is toluene. Preferably, the basic solution issodium bicarbonate.

Preferably, the C₄₋₆ alcohol, used in step b, is t-butanol. Preferably,a mixture of C₁₋₄ alcohol and C₄₋₆ alcohol may be used, in step b,instead of the C₄₋₆ alcohol alone. More preferably, the mixture is thatof methanol and t-butanol.

Preferably, the reducing agent is a metal hydride. Preferably, the metalhydride is selected from the group consisting of NaBH₄, LiAlH₄, andVITRIDE® sodium dihydro-bis-(2-methoxyethoxy)aluminate. More preferably,the reducing agent is NaBH₄.

Combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester areducing agent and a C₄₋₆ alcohol to obtain2(2,3-dihydrobenzofura-5-yl)-ethanol provides a suspension. Preferably,the suspension is heated to a temperature of about 65° C. to about 75°C., more preferably, of about 70° C. to about 75° C. Preferably, theC₁₋₄ alcohol is added drop-wise. Preferably, the drop-wise addition isdone over a period of about 2 to about 6 hours, and more preferably overa period of about 5 to about 6 hours. Typically, adding the C₁₋₄ alcoholprovides a mixture. Preferably, the mixture is maintained for a totaltime of about 5 to about 10 hours, and more preferably for about 5 toabout 7 hours. If the reaction is not completed after 5 to about 10hours, a second amount of a reducing agent can be added. Preferably, thereducing agent is added with a C₁₋₄ alcohol. After the addition of thereducing agent and a C₁₋₄ alcohol, the reaction is further maintained,preferably, for about 1 to about 14 hours, more preferably, for about 2to about 3 hours.

The reaction for preparing 2(2,3-dihydrobenzofura-5-yl)-ethanol mayfurther comprise a recovery step. The recovery done by any method knownto a skilled artisan. According to the process of the present invention,the recovery comprises removing the solvent; adding water and a solventselected from the group consisting of toluene, dichloromethane, andethyl acetate to obtain a mixture having an aqueous phase and an organicphase; separating the aqueous and organic phases; extracting the organicphase with water and a solvent selected from the group consisting oftoluene, dichloromethane, and ethyl acetate; extracting the organicphase with water; and removing the solvent.

Preferably, the C₁₋₂ halogenated hydrocarbon is dichloromethane. Apreferred C₃₋₆ ester is ethyl acetate, isopropylacetate, butylacetate,or isobutylacetate. Preferably, the C₆₋₉ aromatic hydrocarbon istoluene, xylenes, i-propylbenzene, or styrene. The preferred solvent istoluene.

Preferably, the substance containing a leaving group is selected fromthe group consisting of SOCl₂, PCl₃, PCl₅, POCl₃, tosylchloride,mesylchloride, brosylchloride, trifluoroacetyl chloride, andtrifluoromethansulphonyl chloride. Preferably, the substance containinga leaving group is SOCl₂, PCl₃, PCl₅, or POCl₃, more preferably, SOCl₂.Preferably, the substance containing a leaving group is added drop-wise.When the substance containing a leaving group is one of tosylchloride,mesylchloride, brosylchloride, trifluoroacetyl chloride, andtrifluoromethansulfonyl chloride, a base may also be used. Preferably,the base is either an organic or an inorganic base. The organic base maybe, preferably, an aliphatic or aromatic amine. Preferably, thealiphatic amine is triethylamine, ethyldiisopropylamine, orN-methylmorpholine. A preferred aromatic amine is pyridine. Theinorganic base is preferably either an alkali metal hydroxide or analkali metal carbonate. Preferably, the alkali metal hydroxide is sodiumhydroxide, potassium hydroxide, or cesium hydroxide. A preferred alkalimetal carbonate is sodium, potassium, or cesium carbonate. The morepreferred base is an organic base, preferably, triethylamine.

Preferably, combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with asolvent selected from the group consisting of a C₁₋₂ halogenatedhydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, a substancecontaining a leaving group provides a mixture. Preferably, the mixtureis heated to a temperature of about 60° C. to about 80° C., morepreferably, of about 60° C. to about 70° C. The mixture is, preferably,maintained, for about 12 to about 20 hours, more preferably, for about15 to about 18 hours.

The process for preparing the derivative of ethyl-dihydrobenzofuran ofthe formula V may further comprise a recovery step. The recovery done byany method known to a skilled artisan. According to the process of thepresent invention, the recovery comprises cooling the reaction mixtureto a temperature of about 30° C. to about 15° C., preferably, to about25° C. to about 20° C., followed by adding the reaction mixture to abasic solution to form a mixture having an aqueous phase and an organicphase; separating the aqueous and organic phases; extracting the aqueousphase with toluene; washing the organic phase with water; removing thesolvent; and decolorizing the obtained residue. Preferably, the basicsolution is of sodium bicarbonate. Decolorization may be done by anymethod skilled in the art, such as using activated charcoal.

The recovered derivative of ethyl-dihydrobenzofuran of formula V may bepurified by crystallization from methanol/water ormethanol/water/acetone. The process comprises dissolving the derivativeof ethyl-dihydrobenzofuran of formula V in methanol, and adding water ora mixture of water and acetone, followed by maintaining for about anhour to about 3 hours to promote crystallization of the derivative ofethyl-dihydrobenzofuran of formula V. The crystallized derivative ofethyl-dihydrobenzofuran of formula V is then filtered, washed and dried.

The process for preparing the compound of formula IV may furthercomprise a process for converting it to darifenacin bromide.

The transformation of the compound of formula IV to darifenacinhydrobromide comprises hydrolysis of the nitrile group; wherein thestarting material can be the free base of the salt of formula IV or thesalt of formula IV. The hydrolysis may be done by a process comprising:a) heating a suspension of an inorganic base in a protic solvent; b)adding the free base or the salt of formula IV to obtain a mixture; c)heating the mixture of step b, and d) adding HBr to the mixture of stepc.

Preferably, the protic solvent is a C₁₋₁₀alcohol. More preferably, theC₁₋₁₀ alcohol is selected from the group consisting of2-methyl-2-butanol, n-butanol, sec-butanol, n-pentanol, sec-amylalcohol, and cyclohexanol. Most preferably, the C₁₋₁₀ alcohol is2-methyl-2-butanol. Preferably, the inorganic base is an alkali base,more preferably, either NaOH or KOH, and most preferably, NaOH.

Preferably, the suspension is heated to a temperature of about 55° C. toabout 70° C. Preferably, the heated suspension is maintained for about 1to about 2 hours, more preferably, for about 1 to about 1.5 hours, priorto the addition of the free base or the salt of formula IV.

Preferably, the mixture is heated at a temperature of about 100° C. toabout 110° C. Preferably, the heated mixture is maintained for about 20to about 36 hours, more preferably, for about 30 to about 32 hours,prior to the addition of HBr.

The HBr may be added after work-up of the mixture. The work-up may bedone by cooling the heated mixture to a temperature of about 25° C. toabout 15° C., and further combining it with water to form a mixturecomprising of an aqueous and an organic phase, followed by separatingthe aqueous and organic phases. The organic phase is then concentratedto give a residue, which is dissolved in a solvent selected from thegroup consisting of methylethylketone (referred to as MEK), n-butanol,EtOAc, BuOAc, acetone, and toluene. The solution is then filtered toeliminate undissolved particles, and the HBr is added to the filtrate.

Darifenacin hydrobromide may be recovered by concentrating the filtrateafter the addition of HBr, to give solid foam, which is then slurried ina solvent selected from the group consisting of diisopropylether, MEK,n-butanol, EtOAc, BuOAc, acetone, and toluene.

The invention also encompasses another process for the preparation ofdarifenacin hydrobromide comprising: a) combining3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the groupconsisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof, a sulfonyl halide, and a base to obtain1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I, diphenylacetonitrile, and an inorganic base, in an organicsolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, toobtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II;

c) reacting the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrileintermediate of formula II, a bromine acceptor selected from the groupconsisting of phenol and naphthol, and an acid to obtain(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBrd) reacting the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt offormula III with an inorganic base in a solvent selected from the groupconsisting of a water immiscible organic solvent, a polar aproticorganic solvent, water and mixtures thereof to obtain a mixture;e) acidifying the mixture of step d;f) heating the mixture of step e;g) basifying the mixture of step f to obtain

3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of formula XI;

h) combining the 3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine offormula XI,2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII,

and a C₆₋₉ aromatic hydrocarbon to obtain a (S)-darifenamine of formulaVII;

i) admixing the (S)-darifenamine of formula VII with a C₁₋₈ alcohol anda reducing agent to obtain the (S)-darifenacin of formula VIII; and

j) admixing the (S)-darifenacin of formula VIII with HBr to obtaindarifenacin hydrobromide, wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl,wherein Z₁ is an acid. Preferably, X is C₆₋₉ aryl, more preferably,tolyl. Preferably, the acid is either HBr or HCl.

The process can be described by the following scheme:

wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl, preferably, C₆₋₉ aryl,more preferably, tolyl, and Z is an acid, preferably, either HBr or HCl.

The intermediates of formulas I, II, and III may be prepared by theprocesses described above.

The intermediate of formula XI

is prepared by combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrilesalt of formula III,

a solvent selected from the group consisting of a water immiscibleorganic solvent, a polar aprotic organic solvent, water, and mixturesthereof, and an inorganic base, wherein Z₁ is an acid. Preferably, Z₁ iseither HBr or HCl.

Preferably, the water immiscible organic solvent is either a C₆₋₉aromatic hydrocarbon or a C₁₀ halogenated aliphatic hydrocarbon. Apreferred C₁₋₁₀halogenated aliphatic hydrocarbon is C₁₋₅ halogenatedaliphatic hydrocarbon, more preferably, DCM. Preferably, the sulfoxideis C₂₋₅ sulfoxide, more preferably, DMSO. Preferably, the ester is C₂₋₅ester, more preferably, EtOAc. A preferred ketone is C₃₋₆ ketone, morepreferably, MEK. Preferably, the nitrile is C₂₋₄ nitrile, morepreferably, ACN. Preferably, the C₆₋₉ aromatic hydrocarbon is C₆₋₉aromatic hydrocarbon, more preferably, toluene. Preferred mixtures areeither that of toluene and water or that of DCM and water. The morepreferred solvent is water.

Preferably, the inorganic base is an aqueous solution of an alkali base.A preferred alkali base is alkali hydroxide, alkali carbonate, or alkalibicarbonate. Preferably, the alkali hydroxide is either sodium hydroxideor potassium hydroxide. Preferably, the alkali carbonate is eithersodium carbonate or potassium carbonate. A preferred alkali bicarbonateis either sodium bicarbonate or potassium bicarbonate. The morepreferred base is alkali hydroxide, most preferably, sodium hydroxide.

The intermediate, 3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine offormula XI, is then converted to (S)-darifenamine of formula VII.

The invention also encompasses (S)-darifenamine of formula VII.

The new compound, (S)-Darifenamine of formula VII can be used for thepreparation of (S)-Darifenacin hydrobromide.

The intermediate (S)-darifenamine of formula VII is prepared by aprocess comprising: combining3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of formula XI,

2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII.

and a C₆₋₉ aromatic hydrocarbon.

Typically, combining 3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine,the compound of formula XI, 2-(2,3-dihydrobenzofuran-5-yl)acetaldehydeof formula XII, and a C₆₋₉ aromatic hydrocarbon provides a mixture.Preferably, the mixture is maintained at a temperature of about 0° C. toabout 70° C., more preferably, at a temperature of about 10° C. to about40° C. Preferably, the mixture is maintained for about 3 hours to about20 hours, more preferably, for about 10 hours to about 15 hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is selected from the groupconsisting of toluene, xylene, or trimethylbenzene, and more preferablytoluene.

The 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII

is prepared by a process comprising: a) combining2,3-dihydrobenzofura-5-yl-carboxyaldehyde of formula IX,

a C₂₋₄ alkylhaloacetate, an alkoxide, and an alkaline hydroxide toobtain the epoxide of the following formula;

b) admixing the epoxide with a solvent selected from a group consistingof C₆₋₉ aromatic hydrocarbons, C₁₋₂ halogenated hydrocarbons, water, andmixtures thereof, and an acid selected from a group consisting of H₃PO₄,acetic acid, HCl sulfonic acid, and HBr to obtain2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII.

Usually, combining the compound of formula IX and a C₂₋₄alkylhaloacetate provides a solution. Preferably, the solution is heatedto a temperature of about 30° C. to about 60° C., more preferably, toabout 45° C. to about 50° C., prior to the addition of the alkoxide.

Preferably, the C₂₋₄ alkylhaloacetate is 2-butylchloroacetate.

Preferably, the alkoxide is t-butoxide. The alkoxide may be solid or asolution in an alcohol. Preferably, the alcohol is 2-butanol.Preferably, the alkoxide is added portion-wise. Preferably, the solutionof the alkoxide is added over a period of about 0.5 hour to about 1.5hours, more preferably, for about 45 minutes to about 1 hour.Preferably, the alkoxide is added at a temperature of about 30° C. toabout 60° C., more preferably, for about 45° C. to about 50° C.Preferably, a suspension is obtained.

Preferably, the obtained suspension is added slowly to the alkalinehydroxide, providing a mixture. Preferably, the obtained suspension isadded to the alkaline hydroxide over a period of about 1 to about 4hours, and, more preferably, about 1 to about 2 hours. Preferably, thealkaline hydroxide is selected from a group consisting of NaOH, KOH,LiOH, and more preferably, KOH. The alkaline hydroxide may be solid oran aqueous solution, preferably, an aqueous solution. Preferably, theaddition is done at a temperature of about 30° C. to about 60° C., morepreferably, for about 45° C. to about 50° C.

Preferably, after the addition, the mixture is maintained for about 0.5hour to about 1.5 hours, more preferably, for about 45 minutes to about1 hour, thus leading to a thick suspension comprising the epoxide of thefollowing formula;

wherein M is an alkali metal. Preferably, M is selected from a groupconsisting of Na, K, and Li, more preferably, K.

Preferably, the solvent is added to the thick suspension, comprising ofthe epoxide forming a new mixture. The new mixture is cooled.Preferably, the new mixture is cooled to a temperature of about 10° C.to about 0° C., more preferably, to about 5° C. to about 1° C.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. A preferred C₁₋₂halogenated hydrocarbon is dichloromethane. The more preferred solventis toluene.

After cooling, an acid selected from a group consisting of H₃PO₄, aceticacid, HCl, sulfonic acid and HBr is added. Preferably, the acid isH₃PO₄. Preferably, the acid is added drop-wise. Preferably, thedrop-wise addition is done for about 15 minutes to about 2 hours.Preferably, the addition of the acid results in a pH of about 5 to about7, more preferably, about 5.4 to about 5.8. The addition of the acidcauses the suspension to transform to a two phase solution having anaqueous and an organic phase comprising the aldehyde of formula XII.

The process for preparing the 2-(2,3-dihydrobenzofuran-5-yl)acetaldehydeof formula XII may further comprise a recovery process. The recovery maybe done by any method known to a skilled artisan. The recovery may bedone by a process comprising: separating the phases, washing the organicphase with water and then with a saturated NaCl solution, followed byremoving the solvent from the organic phase.

The invention also encompasses2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde-bisulfite complex of formulaX.

The bisulfite complex can be used to purify the aldehyde of formula XII.The process comprises a) combining2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde, a water immisciblehydrocarbon, and Na₂S₂O₅ to form a mixture; and b) admixing with a baseto the mixture to obtain purified2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII.

Preferably, the water immiscible hydrocarbon is either a C₆₋₉ aromatichydrocarbon or a saturated hydrocarbon. Preferably, the C₆₋₉ aromatichydrocarbon is toluene. The more preferred solvent is toluene.

Na₂S₂O₅ may be used in a solid form or in a form of an aqueous solution.Preferably, Na₂S₂O₅ is used in a form of an aqueous solution.

Preferably, the mixture obtained is maintained at a temperature of about15° C. to about 35° C., more preferably, at about 20° C. to about 25° C.Preferably, the mixture is maintained for about 2 hours to about 4hours.

The bisulfite complex can also be used for preparing the compound offormula V. The process for the preparation of derivatives ofethyl-dihydrobenzofuran of the formula

V, from the bisulfite complex comprises combining the bisulfite complexof formula X,

water, NaOH, Na₂CO₃, a water immiscible hydrocarbon, and a reducingagent to form a mixture comprising of the alcohol of the followingformula;

and combining the mixture with a solvent selected from the groupconsisting of C₁₋₂ halogenated hydrocarbons, C₃₋₆ esters, and C₆₋₉aromatic hydrocarbons, and a substance containing a leaving groupselected from the group consisting of Cl, Br, mesyl, brosyl, tosyl,trifluoroacetyl, and trifluoromethansulfonyl to obtain the compound offormula V, wherein Y is a leaving group selected from the groupconsisting of I, Cl, brosyl, Br, mesyl, tosyl, trifluoroacetyl, andtrifluoromethansulfonyl, preferably, Cl.

Preferably, NaOH is added to a suspension of the compound of formula Xin water to obtain a basic mixture comprising2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII. Preferably,the pH of the basic mixture is about 9 to about 11, more preferablyabout 9.5 to about 10.5, and even more preferably about 10 to about10.2.

Preferably, after adjusting the pH, Na₂CO₃ and a water immisciblehydrocarbon are added to obtain a mixture. Preferably, the waterimmiscible hydrocarbon is either a C₆₋₉ aromatic hydrocarbon or asaturated hydrocarbon. Preferably, the C₆₋₉ aromatic hydrocarbon istoluene. A preferred saturated hydrocarbon is either heptane orcyclohexane. The more preferred solvent is toluene.

Preferably, the mixture is cooled to a temperature of about 20° C. toabout 0° C., more preferably to about 10° C. to about 5° C., prior tothe addition of the reducing agent. Adding a reducing agent provides areaction mixture. Preferably, the reducing agent is selected from thegroup consisting of NaBH₄, LiAlH₄, and H₂/Pd. A solution or solid NaBH₄may be used. Preferably, a solution of NaBH₄ is used. Preferably, theNaBH₄ is in solution in water or an alcohol. Preferably, the alcohol isa C₃₋₆ alcohol. The more preferred solvent is water.

Preferably, the solution of the reducing agent is added drop-wise.Preferably, the drop-wise addition is done over a period of about 0.5hour to about 1.5 hours, and more preferably over about 45 to about 60minutes.

Preferably, a pH of about 9 to about 11, more preferably, about 9.8 toabout 10.2 is maintained during the addition.

Preferably, after the addition of the reducing agent, the temperaturewas raised to about 10° C. to about 25° C., more preferably, to about15° C. to about 25° C. Preferably, after raising the temperature, thereaction mixture is maintained for about 0.5 hour to about 1.5 hours,more preferably, for about 1 hour, leading to the corresponding alcoholof the following formula.

Preferably, the transformation of the alcohol to the compound of formulaV is as described before.

The process for preparing (S)-darifenamine of formula VII may furthercomprise a process for converting it to (S)-darifenacin hydrobromide.

The conversion of (S)-darifenamine of formula VII to (S)-darifenacinhydrobromide may be done through the intermediate, (S)-darifenacin offormula VIII.

The intermediate (S)-darifenacin of formula VIII

is prepared by a process comprising combining (S)-Darifenamine offormula VII,

a C₁₋₈ alcohol, and a reducing agent to obtain (S)-darifenacine offormula VIII.

(S)-Darifenacin of formula VIII may be prepared step-wise or in onestep, i.e., without isolation of (S)-Darifenamine of formula VII.Preferably, (S)-Darifenacin of formula VIII is prepared in one step.

Preferably, the reducing agent is added to a reaction mixture comprising(S)-Darifenamine of formula VII.

Preferably, the reducing agent is selected from the group consisting ofNaBH₄, LiAlH₄, and H₂/Pd and more preferably NaBH₄. Preferably, asolution of NaBH₄ in the C₁₋₈ alcohol is used.

Preferably, the C₁₋₈ alcohol is selected from the group consisting ofmethanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol,and hexanol. The more preferred C₁₋₈ alcohol is ethanol.

Preferably, the reducing agent is added portion-wise to a mixture of(S)-Darifenamine and the alcohol, to obtain a reaction mixture.Preferably, the portion-wise addition is done over a period of about 15minutes to about 1 hour, and more preferably for about 20 to about 30minutes.

After the portion-wise addition is complete, the reaction mixture ismaintained for about 2 hours to about 10 hours, more preferably, forabout 2 hours to about 4 hours. Preferably, the mixture is maintained ata temperature of about 0° C. to about 50° C., more preferably, about 10°C. to about 30° C. The reaction may be monitored by HPLC. Preferably,the formation of (S)-Darifenacin is monitored by HPLC.

The process for preparing (S)-Darifenacin of formula VIII may furthercomprise a recovery step. The recovery may be done according to aprocess known to a skilled artisan. The recovery may be done by washingthe reaction mixture with water, followed by removing the solvent.

The (S)-darifenacin of formula VIII may then be converted to(S)-darifenacin hydrobromide, for example, according to the processdisclosed in U.S. Pat. No. 5,096,890.

Preferably, (S)-darifenacin is converted to (S)-darifenacin hydrobromideby a process comprising: adding an aqueous solution of HBr to a solutionof (S)-darifenacin in n-butanol, followed by removing the water toobtain a suspension. The suspension is cooled to induce precipitation ofthe (S)-darifenacin hydrobromide, and the precipitate of (S)-darifenacinhydrobromide is then collected by filtration.

The invention also encompasses a process for preparing oxidizeddarifenacin hydrobromide comprising combining an oxidized derivative ofethyl-dihydrobenzofuran of the following formula

3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of the formula IX

an inorganic base and water; admixing with HBr to obtain oxidizeddarifenacin hydrobromide; wherein Y is a leaving group selected from thegroup consisting of I, Cl, brosyl, mesyl, tosyl, trifluoroacetyl, andtrifluoromethansulfonyl. Preferably, Y is Cl.

The invention also encompasses another process for the preparation ofdarifenacin hydrobromide comprising: a) combining an oxidized derivativeof ethyl-dihydrobenzofuran of the following formula

3-(S)-(+)-(1-carbamoyldiphenylmethyl)pyrrolidine of the formula IX

an inorganic base and water; b) admixing with HBr to obtain oxidizeddarifenacin hydrobromide; and c) admixing with a reducing agent toobtain darifenacin hydrobromide; wherein Y is a leaving group selectedfrom the group consisting of I, Cl, brosyl, mesyl, tosyl,trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is Cl.

Preferably, the inorganic base is K₂CO₃, Na₂CO₃, or Cs₂CO₃.

Preferably, after combining all the above substances, the combination isheated to reflux temperature, more preferably to about 100-120° C.Typically, the combination is heated to induce the formation of oxidizedDarifenacin. Preferably, the combination is heated to for about 5 hoursto about 10 hours.

After obtaining Darifenacin oxide, a work-up of the heated reactionmixture is done. The work-up is done, prior to admixing with HBr.Preferably, the work-up comprises: cooling the heated combination;admixing with C₄₋₈ alcohol, providing a solvent system comprising of atleast a two-phases; separating the phases, and concentrating the organicphase.

Preferably, the heated combination is cooled to a temperature of about90° C. to about 60° C., more preferably, to 90° C. to about 85° C.Preferably, the C₄₋₈ alcohol is n-butanol, i-butanol, amylalcohol,cyclohexanol, or t-butanol. The solvent system having at leasttwo-phases comprises an aqueous phase and an organic phase. Afterseparating the phases, preferably, the organic phase is concentrated bydistillation. Preferably, the concentrated organic phase is admixed withacetic anhydride, prior to the admixing with HBr. The addition of HBrprovides a precipitate of oxidized darifenacin hydrobromide.

The process for preparing oxidized Darifenacin hydrobromide may furthercomprise recovering the oxidized Darifenacin hydrobromide. The recoverycan be done by any process known to a skilled artisan. Preferably, therecovery comprises filtering the precipitate, washing and drying.

The process for preparing the oxidized Darifenacin hydrobromide mayfurther comprise converting oxidized Darifenacin hydrobromide toDarifenacin hydrobromide. The conversion can be done, for example,according to the process disclosed in Example 8 of U.S. Pat. No.5,096,890 (reproduced below as Comparative Example 24).

Typically, oxidized Darifenacin hydrobromide is reduced by reacting witha reducing agent providing Darifenacin hydrobromide. Preferably, thereaction of oxidized Darifenacin hydrobromide and the reducing agent isdone in the presence of an acid. Preferably, the acid is acetic acid.Preferably, the reducing agent is selected from the group consisting ofNaBH₄, LiAlH₄, and H₂/catalyst and more preferably, the reducing agentis a combination of a catalyst and hydrogen gas. Preferably, thecatalyst is palladium, platinum, ruthenium, rhodium, or nickel. Morepreferably, the palladium is absorbed on charcoal.

Typically, the reaction is done under heating. Preferably, the heatingis to a temperature of about 45° C. to about 50° C. Preferably, thehydrogen gas is present at atmospheric pressure.

Preferably, the reaction is maintained for about 6 to about 7 whereinthe formation of Darifenacin hydrobromide is expected.

The process for preparing Darifenacin hydrobromide may further comprisea recovery step. The recovery can be done by any process known to askilled artisan. Preferably, the recovery is done by filtering thecatalyst; concentrating the filtrate; admixing the concentrated filtratewith n-butanol and HBr to obtain a mixture, and concentrating themixture to obtain a precipitate of Darifenacin hydrobromide.

Preferably, the mixture is concentrated to obtain a filtrate having lessthan 1% of water.

The obtained precipitate can be isolated by filtration, washing anddrying. Having described the invention with reference to certainpreferred embodiments, other embodiments will become apparent to one ofordinary skill in the art from consideration of the specification. Theinvention is further defined by reference to the following examples. Itwill be apparent to those of ordinary skill in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

EXAMPLES Example 1 Preparation of 1-tosyl-3-(S)-(−)tosyloxypyrrolidine(Formula I)

(S)-3-pyrrolidinol (30 g, 0.344 moles) was dissolved in toluene (150 ml)and tetrabutylammonium bromide (3.39 g, 0.0105 moles) was added to thesolution. p-Toluensulfonylchloride (140.94 g, 0.7393 moles) was thenadded portion-wise to the solution, causing the temperature of thesolution to rise to 35 to 40° C. Then, 30% NaOH (112.1 g, 0.8407 moles)was slowly added to the solution over about 1 hour, causing thetemperature of the solution to rise to 55 to 60° C. After maintainingthe solution for 5 hours at 55-60° C., the reaction was complete. Water(30 ml) was then added, and the resulting suspension was cooled to 0° C.over 1 hour to give a solid. The solid was filtered and washed with coldtoluene and water to give the title compound. (Dry weight 127.95 g,yield 94%, HPLC purity 99.2% area). The main impurity is1-tosyl-3-(S)-pyrrolidinol (reaction intermediate) in an amount of 0.05%area by HPLC.

Example 2 Preparation of(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (Formula II)

Diphenylacetonitrile (63.7 g, 0.3296 moles) was dissolved in DMF (395ml), followed by adding sodium tert-butylate (31.75 g, 0.33 moles),which caused the temperature of the solution to rise to 35° C. Aftercooling the solution to 20° C., 1-tosyl-3-(S)-(−)tosyloxypyrrolidine(126.5 g, 0.3198 moles) was added. The solution was warmed to 70 to 75°C., and, after maintaining the solution at 70 to 75° C. for 4 hours, thereaction was complete. Water (250 ml) and toluene (500 ml) were thenadded to the solution to form a two phase mixture having an aqueous andan organic phase. The phases were stirred at 70° C. and separated. Theaqueous phase was extracted with toluene (50 ml), followed by washingthe combined organic phases three times with water (100 ml each), andconcentrating under vacuum to give a 250 ml residual volume. Theresidual volume was cooled to 0° C. to obtain a precipitate. Theprecipitate was filtered and washed with toluene and water to give thetitle compound. (Dry weight 116 g, yield 86.5%, and HPLC purity 99.3%area). The main impurities present are residual starting materials:diphenylacetonitrile and N—O-ditosyl-3-(S)-pyrrolidinol in amounts of0.1% area by HPLC each.

Example 3 Preparation of (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrilehydrobromide(S-DIPACP.HBr) (Formula III)

In a 2 l reactor equipped with mechanical stirrer, thermometer andcondenser load under nitrogen HBr 48% (1.100 ml), Phenol (44.08 g),S-DIPACP-N-Tosyl[(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile] (220 g) wereloaded under nitrogen. The suspension was warmed to reflux (118-120° C.)to obtain a biphasic system. After 1 hr, the reaction was complete(residual starting material 0.33%). The reaction mixture was then cooledto 25-30° C. and dichloromethane (478 ml) was added. After stirring (5min) the phases were separated (organic phase is upper layer) and theaqueous phase was extracted with dichloromethane (100 ml) and the phasesagain separated (organic phase is upper layer). The collected organicphases were concentrated to 280-290 ml by solvent distillation atatmospheric pressure obtaining an oily residue (T_(int) 64° C.).Maintaining internal temperature at 65-70° C. ethylacetate (287 ml) wasslowly added to the residue. (It is necessary to maintain temperatureand to add ethyl acetate slowly to avoid sudden productcrystallization). Distillation was continued at atmospheric pressure toreach a volume of 380-390 ml (T_(int) 80° C., T_(head) 70° C.). Ethylacetate (191 ml) was added to the obtained suspension and distillationwas continued at atmospheric pressure to reach a volume of 380-390 ml(T_(int) 84° C., T_(head) 72° C.). Repeated distillations are necessaryto eliminate as much dichloromethane as possible in such a way as toincrease yield. The suspension was cooled at 50-55° C. and ethyl acetate(300 ml) was added. The suspension was cooled to 20-25° C. and after 1hr, was cooled to −7-8° C. After 2 hrs, the suspension was filtered andwashed three times with cold ethyl acetate (95 ml) each. After washings,the product became white (initially it was pink). The wet product wasdried under vacuum at 50-55° C. for 6-7 hrs to obtain the titlecompound. (Dry weight 166.3 g, yield 87.4%, HPLC purity 99.93% area).

Example 4 (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromideUsing β-Naphtol as Bromine Acceptor (Formula III)

(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (5 g, 0.0120moles) was added to 48% HBr (25 ml) together with β-naphtol (1.73 g,0.0120 moles), to give a suspension. The suspension was warmed to reflux(117-120° C.), and, after 1 hour the reaction was complete. Aftercooling to 30° C., dichloromethane (10 ml) was added, and the mixturewas stirred for 5 minutes. The phases were separated, and the aqueousphase was extracted with dichloromethane (5 ml). The combined organicphases were washed with saturated solution of NaCl, and thenconcentrated under vacuum to give a residual volume of 10 ml.

Ethyl acetate (10 ml) was added to the residual volume, and thedistillation was continued at atmospheric pressure until a residualvolume of 8 ml was obtained. Ethyl acetate was added, and thedistillation continued until the dichloromethane was eliminated(residual volume 8 ml). Ethyl acetate (15 ml) and hexane (10 ml) wereadded to give a suspension. The suspension was cooled to 0° C. for 2hours to give a precipitate that was filtered and washed with ethylacetate to give the title compound. (Dry weight 3.0 g; yield 72.4%).

Example 5 Preparation of(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilehydrobromide (Formula III)

Potassium carbonate (14.94 g, 0.1081 moles) was dissolved in water (45ml), followed by adding (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrilehydrobromide (18.55 g, 0.0540 moles) and5-(2-bromoethyl)-2,3-dihydrobenzo[2,3-b]furan (13.5 g, 0.05945 moles) togive a suspension. The suspension was warmed to 75° C., and, after 4hours, the reaction was considered to be complete (unreacted startingmaterial 1.5% area by HPLC). The heterogeneous mixture was cooled to 25°C. and ethyl acetate (100 ml) was added. After stirring, the phases wereseparated, the organic layer was washed with water, and the phasesseparated. 48% hydrobromic acid (9.6 g, 0.05668 moles) was added, and(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilehydrobromide was crystallized from the suspension. The suspension wascooled to 15-18° C. for one hour, and the precipitate was filtered andwashed with ethyl acetate to give the title compound. (Dry weight 23.8g; yield 89.93%).

Example 6 Preparation of3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidinehydrobromide (Formula III)

KOH (1.95 g, 0.03134 moles) was added to 2-methyl-2-butanol (7 ml), toobtain a suspension. The suspension was warmed to 60° C. for 1 hour,followed by adding(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilehydrobromide (1 g, 0.00204 moles), and warming the reaction mixture(suspension) to reflux for 21-22 hours. After cooling, water (5 ml) wasadded to the reaction mixture to form a two-phase mixture, and thephases were separated. The solvent was distilled from the organic phaseunder vacuum, and a residue (0.900 g) was obtained and dissolved inmethylethylketone (3 ml). The solution was filtered to eliminateundissolved solid, and 48% HBr (0.344 g, 0.00204 moles) was added. Thesolvent was distilled under vacuum, and a solid foam was obtained. Thefoam was slurried in diisopropylether, filtered, and washed to give thetitle compound. (Dry weight 0.750 g; yield 72%).

Example 7 Preparation of3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine Tartrate (FormulaVI)

3-(S)-(+)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine hydrobromide (80 g0.2330 moles) was converted into its corresponding free base by treatingwith dichloromethane (400 ml), water (150 ml) and 30% NaOH (35 g). Afterphase separation and evaporation of the solvent from the organic phase,an oil residue was obtained. The oil residue was added to 90% H₂SO₄ (130ml), and the mixture was heated to 100° C. for 17 hours. After cooling,the mixture was neutralized with sulfuric acid until a pH of 12 wasobtained. The product was extracted with dichloromethane (250 ml). Afterwashings with water, the solvent was evaporated by distillation, and theproduct was obtained as a foam (45.7 g). The foam was dissolved in 96%ethanol (460 ml), and L-Tartaric acid (26.9 g) was added, followed bycooling to 0° C., to induce crystallization of the tartrate salt. Thesalt was filtered after 1 hour, and washed with 96% ethanol to give thetitle compound. (Dry weight 64.5 g; yield 64.5%).

Example 8 Preparation of3-(S)-(+)-(1-carbamoyl-1,diphenylmethyl)pyrrolidine Tartrate (FormulaVi) a) Free Base Preparation

A four necked round bottomed flask equipped with a thermometer,mechanical stirrer and condenser was charged, under N₂, with3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine hydrobromide (96g), Dichloromethane (280 ml), and water (20 ml). The temperature wasmaintained at 25-30° C. during the loading of NaOH 30% (41.2 g). Theobtained heterogeneous system was stirred for 5 min. and the phases wereseparated. The organic phase was washed with water (41.2 ml), and thephases were separated. The organic phase was concentred under vacuumuntil a final volume of 120 ml was obtained.

b) Hydrolysis Reaction

A four necked round bottomed flask equipped with thermometer, mechanicalstirrer and condenser to eliminate dichloromethane by distillation, wascharged under N₂ with H₂SO₄ 90% (180 ml).

The sulfuric acid solution was warmed to 50-55° C., and the organicsolution obtained above (120 ml) was added slowly allowingdichloromethane elimination by distillation. During the addition themixture was warmed continuously to maintain an internal temperature of60-65° C. When dichloromethane distillation stopped, the internaltemperature was raised to 98-102° C. allowing residual dichloromethaneelimination by distillation. Then, the temperature was maintained at98-102° C. for 14-14.5 hrs.

The reaction mixture was cooled to 25-30° C. and added slowly to amixture of NaOH 30% (958.3 g), water (720 g), and toluene (480 ml),allowing the internal temperature to reach 55-60° C. After stirring at55-60° C. the phases were separated at 55-60° C. The aqueous phase wasbeen extracted at 55-60° C. with toluene (160 ml).

The collected organic phases, maintained at 60-65° C., were washed at60-65° C. with water 240 ml, and then n-butanol (200 ml), water (20 ml)and L-tartaric acid (42.05 g) were added to the separated organic phaseat 45-65° C. The mixture was stirred at 45-65° C. until the L-tartaricacid was almost completely dissolved. At the same time a formation of asalt was detected, at the beginning as a white oil, and then as whitesolid. The suspension was cooled to 15-25° C. and filtered after twohours. When the suspension was too sticky it was found useful to warm to60-65° C. and after 10-15 min to cool to 15-25° C. and filter. The cakewas washed three times with n-butanol (50 ml each), and after 15 hrs ofdrying at 50-55° C. under vacuum 107 g of the title compound wasobtained. (Yield: 88.9%. HPLC purity: 99.88% area).

Example 9 Preparation of 2(2,3-Dihydrobenzofura-5-y)Acetic Acid, MethylEster

98% H₂SO₄ (2 g) was added to a solution of2(2,3-Dihydrobenzofura-5-y)acetic acid (200 g) in MeOH (500 ml), and themixture was refluxed for 3 hrs (TLC: SiO₂, toluene/AcOEt 8:2; startingmaterial not detected). After cooling to room temperature, NaHCO₃ (6.7g) was added to the reaction mixture, and the solvent was distilled offat atmospheric pressure (about 440 ml), to give a light pink oilyresidue.

The oily residue was dissolved in toluene (250 ml), and washed withNaHCO₃ 6% (50 ml). After the phases were separated, the solvent waseliminated under vacuum distillation to obtain a light pink oily residue(227 g).

Example 10 Preparation of 2(2,3-Dihydrobenzofura-5-y)ethanol

2(2,3-Dihydrobenzofura-5-y)acetic acid, methyl ester (227 g residue) wasdissolved in t-BuOH (600 ml), and then NaBH₄ (46.8 g) was added. Thesuspension was warmed to reflux and methanol (100 ml) was added veryslowly in about 6 hrs maintaining reaction mixture at reflux. After themethanol addition, the reaction was maintained at reflux for half anhour (in process control revealed complete ester transformation). 400 mlof the t-BuOH-MeOH mixture was distilled off at atmospheric pressure.Water (400 ml) was added to residue and the distillation continued untilT_(int)=93° C. and T_(head)=83° C. Water (400 ml) was added, and thedistillation continued until T_(int)96° C. and T_(head)=96° C. Thereaction mixture was cooled to 70-75° C. and toluene (300 ml) was added.The separated organic phase was washed with water (100 ml) and NaCl 15%(100 ml). After the solvent was eliminated under vacuum distillation, anoily residue (176.8 g) of the title compound was obtained. The residuesolidified upon cooling.

Example 11 2(2,3-Dihydrobenzofuran-5-y)Ethylchloride

SOCl₂ (74.7 g) was added to a solution of 2(2,3-Dihydrobenzofura-5-y)ethanol 80 g in toluene (400 ml) while maintaining the temperature below25° C. The reaction mixture was stirred at 60° C. for 14 h and thencooled to room temperature. A reaction sample was quenched into 10%Na₂CO₃ (Residual 2(2,3-Dihydrobenzofura-5-y) ethanol 0.6% area by HPLC),and the pH was adjusted to 10-11 (measured on aqueous phase) by additionof 10% NaOH (about 480 ml) while maintaining the temperature below 30°C. The organic phase was separated. The aqueous phase was extracted withtoluene (50 ml). The collected organic phases were washed twice with H₂O(100 ml each) and anhydrified under vacuum distillation (residualpressure 40-50 mm Hg, T_(int) 50-55° C.). To the organic phase, 20 g ofTONSIL® silicate decolorizing agent and 4.2 g of ANTICHROMOS charcoalwere added, stirred for 30 min at room temperature, filtered off andwashed with toluene (2×30 ml), the decolorized solution was concentratedunder vacuum (residual pressure 40-50 mm Hg, T_(int) 50-55° C.) toeliminate toluene. Water (25 ml) was added to obtain a residue, and theresidual toluene was eliminated by azeotropic distillation under vacuum(residual pressure 40-50 mm Hg, T_(int) 50-55° C.). This residue wasdissolved in methanol (373 ml) and charcoal (2 g) were added. After 20minutes at 50-55° C. charcoal was filtered off and washed with hotmethanol (2×10 ml). The obtained decolorized solution was cooled at20′-30° C., and 2(2,3-Dihydrobenzofuran-5-y) ethylchloride crystallizedin the suspension. Water (280 ml) was added to the suspension at 25′-30°C. over about 60 min to obtain a sticky, but stirrable, suspension.After 1 hr at 20-25° C. the solid was filtered, and washed three timeswith MeOH-Water 1:1 (20 ml each). The wet solid was dried at 35-40° C.max for 15 hrs to give the title compound. (Dry weight 81.8 g. Yield92%. HPLC purity 99.2% area).

Example 12 Preparation of (S)-Darifenacin Hydrobromide

A 50 ml reactor was loaded with—(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine Tartrate (4 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and water (12.5ml), to obtain a heterogeneous mixture. The heterogeneous mixture washeated to reflux (103° C.) for 2.5 hours. After cooling,dichloromethane, EtOAc or BuOAc (15 ml) were added, and, after stirring,the phases were separated. Acetic anhydride (0.5 ml) was added to theorganic phase, and, after 1 hour at room temperature, the residual3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was transformedinto N-Acetyl derivative. The solvent was removed by distillation, andn-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72g) was also added, and the residual DCM was removed under vacuumdistillation. In the case of EtOAc or BuOAc, distillation under vacuumis useful to eliminate water. Darifenacin hydrobromide crystallized,and, after cooling to room temperature, the darifenacin hydrobromide wasfiltered and washed. (Wet solid 4.17 g).

Example 13 Preparation of (S)-Darifenacin Hydrobromide

A 50 ml reactor was loaded with(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine free base (2.6 g,9.29 mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and water (12.5 ml)to obtain a heterogeneous mixture. The heterogeneous mixture was heatedto reflux (103° C.) for 2 to 5 hours. After cooling, dichloromethane,Ethyl acetate, or Butylacetate (15 ml) was added, and, after stirring,the phases were separated. Acetic anhydride (0.5 ml) was added to theorganic phase, and, after 1 hour at room temperature, the residual3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was transformedinto N-Acetyl derivative (as described in example 11). Half of thesolvent was removed by distillation, and n-butanol (25 ml) was added tothe residue. 48% hydrobromic acid (1.72 g) was also added, and theresidual DCM was removed under vacuum distillation. In the case of EtOACor BuOAc, distillation under vacuum is useful to eliminate water.Darifenacin hydrobromide crystallized, and, after cooling to roomtemperature, the darifenacin hydrobromide was filtered and washed. (Drysolid 2.5 g).

Example 14 Preparation of (S)-Darifenacin Hydrobromide

A 150 ml reactor was loaded with water (37.5 ml), potassium carbonate(12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride (DBF-EtCl) (5.48g). The mixture was warmed to 60-65° C. and DBF-EtCl melted. Then,(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (12 g) wasloaded and the heterogeneous mixture was warmed to reflux (101-102° C.)for 5 hrs.

The reaction mixture was cooled to 80-85° C. and n-butanol (60 ml) wasadded. The internal temperature was maintained at 75-80° C., and themixture was stirred until complete dissolution was obtained. Then, themixture was cooled to 25-30° C. and the phases were separated. Theorganic phase was washed twice with water (30 ml) and the phases wereseparated.

Water was removed by vacuum distillation until a residual volume of 60ml was obtained, and then n-butanol (30 ml) was added. Then, aceticanhydride (0.6 ml) was loaded and the mixture was stirred at 20-30° C.for 1 hr, followed by loading HBr 48% (4.7 g) at 25-27° C. The water and20 ml of butanol were removed by vacuum distillation to obtain asuspension of darifenacin hydrobromide. The suspension was stirred at25-30° C. for 2 hrs, and then cooled to 0-5° C., and filtered after 1hr. The cake was washed with cold n-Butanol (3×3 ml), and dried undervacuum at 50-55° C. for 6-7 hrs. (Dry weight 11.2-11.5. Yield 79-81%).

Example 15 Crystallization of (S)-Darifenacin Hydrobromide

A 100 ml reactor was loaded with crude darifenacin hydrobromide (10 g),n-butanol (70 ml), and charcoal (0.3 g). The mixture was warmed toreflux to obtain a solution. The charcoal was filtered at reflux andwashed with n-butanol (5 ml).

The solution was maintained at 100° C. and seeded to inducecrystallization. After 30 min at 100° C., the mixture was cooled to 0°C. over 3 hrs, and after 1 hr at 0° C. the mixture was filtered. Theproduct was washed with cold butanol (3×3 ml). (Dry weight 8.8-8.9 g.Yield 88-89%. HPLC purity 99.65-99.75% area).

Example 16 Preparation of (S)-Darifenacin Hydrobromide Via(S)-Darifenamine

3-(S)-(+)-(1-Carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.1 g, 7.5mmoles) and 2,3-dihydrobenzofuran-5-yl, acetaldehyde (1.4 g, 8.6 mmoles)were combined with toluene (20 ml) at room temperature, and reacted for15 hours to give (S)-darifenamine.

At this point, a solution of NaBH₄ (0.57 g, 15 mmoles) in ethanol (10ml) was added slowly, and after 3 hours at room temperature, HPLCanalysis revealed formation of (S)-Darifenacin. After washing withwater, the solvent was eliminated by distillation, and the obtainedresidue was dissolved in n-BuOH followed by the addition of HBr 48% (1.5g, 9 mmoles). Water was eliminated under vacuum, and a slowcrystallization was observed. After cooling, the product was filteredand washed with n-BuOH to give the title compound. (Dry weight 0.7 g).

The same reaction has been performed in presence of molecular sieves andtitanium isopropylate with similar results.

Example 17 Purification of Darifenacin HBr

The product of Example 16 (3.6 g) was suspended in n-Butanol (25 ml),and heated to reflux to obtain a solution. Charcoal (0.1 g) was added,and, after 5 minutes at reflux, was filtered off. After cooling to roomtemperature, Darifenacin HBr was filtered, washed, and dried at 45-50°C. under vacuum for 10 hours. (Dry solid 3.20 g; overall yield 68%; HPLCpurity 99.86% area).

Example 18 2,3-Dihydrobenzofura-5-yl, Acetaldehyde

In a four necked round bottomed flask equipped with thermometer,mechanical stirrer and condenser, was charged under N₂,2,3-Dihydrobenzofura-5-yl, carboxaldehyde (50 g, 0.33 moles) and2-butylchloroacetate (66.5 g, 0.4415 moles). The solution was warmed to40-45° C., followed by a dropwise addition (in about 1 hour) of 288 mlof 17% (w/v) potassium 2-butylate solution in 2-butyl alcohol (0.43moles). The reaction was maintained at a temperature of 40-45° C., andafter 1 hour at 40-45° C., HPLC analysis revealed almost completetransformation of carboxaldehyde. The suspension was slowly added to asolution of KOH 90% (24.5 g, 0.3937 moles) in water (47 ml), followed bymaintaining at 45-50° C. After 1 hour at 45° C., TLC analysis revealedcomplete hydrolysis, and a thick suspension was obtained. At this pointtoluene (120 ml) and water (180 ml) were added, and the suspension wascooled to 1-5° C. Then, 75% H₃PO₄ (about 50 g) was added drop-wise toobtain a pH in range of 5.4-5.8. During acidification CO₂ evolves andalmost complete solid dissolution is observed. After the phases areseparated, the organic phase was washed with water (200 ml) and thenwith sat NaCl, (100 ml). After solvent elimination under vacuum, aresidual oil (47 g) of the title compound was obtained. (GC purity 91%.)

Example 19 2(2,3-Dihydrobenzofura-5-y) Acetaldehyde, Bisulfitic Complex

In a four necked round bottomed flask equipped with thermometer, andmechanical stirrer, was loaded 2,3-Dihydrobenzofura-5-yl, acetaldehyde,of example 18 (47 g, 0.29 moles) and toluene (500 ml) to obtain asolution. Then, water (100 ml) and Na₂S₂O₅ (58.6 g) were added. Thebisulfitic adduct precipitated and after 3 hours at room temperature itwas filtered and washed twice with toluene (50 ml each). (Wet product:95 g).

Example 20 2(2,3-Dihydrobenzofura-5-y)Ethanol

The obtained wet bisulfitic adduct of example 19 was suspended in water(150 ml), and the pH was adjusted to 10-10.2 with NaOH 30%. Na₂CO₃ 10%(50 ml) and toluene (100 ml) were added and, after cooling to 5-10° C.,a solution of NaBH₄ (5.8 g, 0.1526 moles)) in water (40 ml) was addeddrop-wise over about 45-60 minutes, while maintaining the pH at9.8-10.2. The temperature was raised to 15-20° C. and after 1 hour thephases were separated. The aqueous phase was extracted with toluene (25ml), and the combined organic phases were washed with water (50 ml). Thesolvent was eliminated under vacuum distillation, and the obtained oilsolidified to give the title compound (26 g).

Example 21 Synthesis of(S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide

S-DIPAMP tartrate (12 g); BF-EtCl (5.6 g) K₂CO₃ (12 g) and Water 37.5 mlwere heated at reflux for 5 hrs. After cooling to 85-90° C. n-butanol(60 ml) was added. After phases separation and washings (2×30 ml water)the organic phase was anhydrified by distillation and treated with Ac₂O(0.65 ml) for three hrs. 48% HBr was added slowly and DRF-Ox-HBrcrystallized. After 2 hrs at 15° C. the solid was filtered and washedwith Butanol (3×5 ml). Wet solid was dried under vacuum at 50-55° C. for15 hrs. (Dry weight 8.8 g).

Example 22 Synthesisof(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide(DRF.HBr)

Pd/C 10% (0.8 g) was added to a solutionof(S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide(8 g) in acetic acid (160 ml). The mixture was hydrogenated at 45-50° C.and at atmospheric pressure for about 6-7 hrs. Catalyst was filtered offand solution was concentrated under vacuum obtaining an oily residue.n-Butanol (40 ml) was added and stirred to obtain a solution. 48% HBr(3.5 g) was added and a mixture n-Butanol/water was eliminated bydistillation to reduce water content to less then 1%. Darifenacin .HBrcrystallizes and after 2 hrs at 15-20° C. was filtered and washed withn-Butanol (3×5 ml). After drying at 55-60° C. under vacuum 8.1 g ofDarifenacin hydrobromide were obtained. (Yield 85%).

Example 23 Preparation of Darifenacin Hydrobromide

Water (ml 203) Potassium carbonate (g 65) and DBF-EtCl (g 29.7) wereheated to 60-65° C. To the mixture (S)-DIPAMP Tartrate (g 65) was addedand the heterogeneous mixture was heated to reflux (101-102° C.) for 5hrs. After cooling to 85-90° C. n-Butanol (ml 325) was added and afterstirring phases were separated.

The organic phase was washed twice with water ml 160 (each) and thenwater was removed from organic phase by vacuum distillation. n-Butanol(ml 160) and Acetic anhydride (ml 3.25) were added and the solution wasstirred at 20-30° C. for 1 hr. 48% HBr (g 25.5) was dropped, water wasremoved by vacuum distillation and DRF-HBr crystallized. Initial volumewas restored by addition of n-BuOH. Suspension was stirred at 15-20° C.for 2 hrs, than product was recovered by filtration. The cake was washedwith n-Butanol (3×30 ml) and wet solid (85-90 g) was crystallizedwithout drying.

Crude wet DRF-HBr (85 g), n-Butanol (455 ml) and charcoal (4.63 g) werewarmed to reflux to obtain a solution. After half an hour charcoal wasfiltered off keeping mixture at near reflux. Clear solution at 100° C.was seeded with DBR.HBr and after 30 min at 100° C. the solution wascooled to 15-20° C. in 2 hrs. Suspension was stirred at 15-20° C. for 2hrs and then product was recovered by filtration. Cake was washed withn-butanol (3×25 ml). Wet pure DRF-HBr was dried under vacuum at 50-55°C. for 10-12 hrs. Dry weight 59.2 g. Overall Yield 77.2%

Comparative Example 24 Example 8 from U.S. Pat. No. 5,096,890 (col. 12,11. 1-52) Preparation of3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine (Alternative to Example 1(B))

10% Palladium-on-carbon (10 mg) was added to a solution of3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(benzofuran-5-yl)ethyl]pyrrolidine(0.1 g—see Example 7) in acetic acid (2 ml) and the mixture washydrogenated at 40° C. and atmospheric pressure for 6 hours. Thecatalyst was filtered off and washed with water (20 ml). The combinedfiltrate and washings were transferred to a separating funnel,dichloromethane (20 ml) was added, and the mixture was basified by theaddition of 10% aqueous sodium hydroxide. The layers were separated andthe aqueous layer was further extracted with dichloromethane (3×30 ml).The combined dichloromethane extracts were dried (MgSO₄) andconcentrated in vacuo to give a colourless solid which was purified bycolumn chromatography on silica eluting with dichloromethane containingmethanol (4%). The product-containing fractions were combined andconcentrated in vacuo to give the title compound as a colourless glass,yield 0.048 g, which was characterised spectroscopically to be identicalto the product of Example 1(B).

1H-N.M.R. (CDCl₃), δ=7.50-7.20 (m, 11H); 7.00 (s, 1H); 6.90 (d, 1H);6.70 (d, 1H); 5.45-5.30 (brs, 1H); 4.60-4.50 (t, 2H); 3.60-3.45 (m, 1H);3.25-3.15 (t, 2H); 3.05-2.50 (m, 8H); 2.10-1.95 (m, 2H) ppm.

While it is apparent that the invention disclosed herein is wellcalculated to fulfill the objects stated above, it will be appreciatedthat numerous modifications and embodiments may be devised by thoseskilled in the art. Therefore, it is intended that the appended claimscover all such modifications and embodiments as falling within the truespirit and scope of the present invention.

1. 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde-bisulfite complex offormula X